Age-related macular degeneration (AMD) is the leading cause of irreversible severe central visual loss in the aged population. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation causes predisposition to the disease. We initiated the project in early 2003 by recruiting advanced AMD patients and normal controls. So far over 400 subjects have been enrolled and 53 histopathological cases with AMD were collected. We also received 835 DNA smaples from Blue Mountain Eye Study in Australia and 534 DNA smaples from AREDS. We are comparing the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects followed by the functional study of these SNPs by in vitro and/or in vivo experiments. Through this approach, we identify genetic risk factors of AMD and understand the role of these gene variations in the pathogenesis of the disease. Based on the information obtained from above experiments and recent literature, gene engineered animal are generated to establish the disease model. In FY2006, we have accomplished the following: 1. Completion of 15000 SNPs typing; 2. Report of synergic effect of polymorphisms in ERCC6 5' flanking region and complement factor H on AMD predisposition; 3. Characterization of the retinal lesion of the CX3CR1/CCL2 double knock-out mice, a murine model of AMD, which we developed; 4. Confirmation of LOC association with AMD; and 5. Confirmation of the involvement of ER protein in the pathogenesis of retinal digeneration. Four articles were published and 9 abstracts wre presented in various meetings including FASEB, ARVO and Global Chinese Ophthalmological Conference in this time period. We are preparing several more manuscripts.